Dr. Hakan ÖZÖRNEK EUROFERTIL Reproductive Health Center

OHSS OHSS is an iatrogenic complication of ovulation induction. The syndrom can result in serious life treatening complications The syndrom charecterized by leakage of fluid from the intravascular compartment, with accumulation in the peritoneal and pleural cavities, resulting in hypotension and a decrease in renal blood flow and volume of urine.

Classification Mild OHSS Moderate OHSS Severe OHSS Grade 1 Abdominal distention and discomfort Grade 2 + nausea, vomiting and/or diarrhoea Moderate OHSS Grade 3 + ultrasonic evidence of ascites Severe OHSS Grade 4 + clinical evidence of ascites and/or hydrothorax or dyspnoea Grade 5 + haemoconcentration, coagulation abnormalities, diminished renal perfusion

Prevention 1. Step Identification of risk factors 2. Step Monitoring the ovarian response (US+E2)

Risk factors for OHSS PCOS High number of antral follicles at day3 (>10/ovary) Enlarged ovarian volume LH/FSH > 2 Hyperandrogenism Young age < 35 Low body weight Previous ocurrence of OHSS

Prevention by PCOS Diet – weight lose Metformin Ovarian drilling Nonstimulated – natural cycle IVM Oral ovulation induction Low dose gonadotropin

Metformin No metformin (n=159) Metformin (n=128) Age 34.8 33 BMI 27.2 27.8 HMG ampoules 37.1 41.1 Oocytes retrieved 23.8 18.8 Embryos tranferred 2.8 3 Clinical pregnancies 37.6 30.5 Moderate and severe OHSS* 20 1 Khattab, Reprod Biomed Online, 2006

Prevention of OHSS Withholding hCG ‘cancelling’ Delaying hCG ‘coasting’ Modification of methods to trigger ovulation Early unilateral follicular aspiration Progesterone for luteal phase support Cryopreservation of all embryos Gradual and slow hMG protocol in PCOS Albumin administration at time of retrieval Glucocorticoid administration

Canceling Cycles hCG triggers the development of OHSS Withholding hCG is the only method that totally avoids the risk of OHSS Serum E2 level upper limit 4000 pg/ml After stopping the gonadotrophin treatment the GnRH agonist or antagonist should be continiued until the ovaries recover to normal size

Modification of methods to trigger ovulation Decrease in hCG dose 10.000 IU vs. 5.000 IU or 3.000 IU no difference GnRHa Used in antagonist cycle, as effective as hCG, decreased insidence of OHSS but significant less pregnancy rLH PRT multicenter hCG vs rLH significantly fewer moderate and severe cases of OHSS rhCG

Folicular aspiration Folicular aspiration at the time of oocyte retrieval had no protective effect of OHSS Unilateral folikular aspiration prior to HCG also does not reduce the incidence of severe OHSS

Glucocorticoid administration Methylprednisolon (n=50) Untreated (n=41) Age 30.5 30.9 E2 concentration* pg/ml 4848 3727 Oocytes retrieved* 28.7 24 Embryos transferred 3.9 4.0 OHSS* 10% 43.9% Because of conflicting reports in the literature there are currently insufficient data to recommend glucocorticoid administration Lainas et al., Fertil Steril, 2002

Lutheal phase support Lutheal phase support with hCG increases the incidence of OHSS. Progesterone intravaginally or im should be used for the patients at risk of OHSS

Coasting First described and applied by Sher et al in 1993 hCG administration postponed until the patients serum E2 level decreases to a safer zone. Significantly higher percentage of granulosa lutein cells become apoptotic after coasting. E2 levels usually to rise rapidly in the 48 h following initiation of the coasting period, then plateaued and began to fall 96-168 h after the gonadotropins were stopped.

Coasting Cochrane review identified 13 studies of which only one trial met the inclusion criteria. There was no difference in the incidence of moderate and severe OHSS and in the clinical pregnancy rate between the groups. D’Angelo et al., Cochrane Library, 2002

Coasting < 4 days (n=983) Coasting >4 days (n=240) Coasting duration Coasting < 4 days (n=983) Coasting >4 days (n=240) Age 30.2 29.9 Oocytes retrieved* 16.5 14.9 Mean no of embryos trans 2.99 3.03 Clin pregnancy rate* 52.0 35.9 Implantation rate* 26.3 18.2 Mansour, et al., Fertil Steril, 2005

Coasting (Practical guidelines) Start at Serum E2>4500 pg/ml > 15 and < 30 mature follicles Measure E2 on a daily basis, do not skip any day to avoid sudden unexpected drops Give hCG when E2 level falls to < 3500 pg/ml Abandone if E2 level rises to >6500 pg/ml > 30 mature follicles Coasting takes > 4 days

Coasting Coasting is a good alternative that can avoid cycle cancellation in high responders, who have high risk of developing severe OHSS Even if OHSS develops after coasting both its incidence and severity will be diminished

Cryopreservation of all embryos Insted of canceling the cycle after the administration of hCG retrieve the oocytes and than cryopreserve all embryos Cochrane review identified 17 studies, two of which met the inclusion criteria. When elective cryopreservation was compared with fresh embryo transfer no difference was found between the two groups in the incidence of OHSS. There is insufficient evidence to support routine cryopreservation. D’Angelo et al., Cochrane Library, 2002

Albumin administration Albumin is prevent the development of OHSS by increasing plasma oncotic pressure and binding of OHSS mediators of ovarian origin The cochrane review shows a clear benefit from administration of iv albumin at te time of oocyte retrieval in prevention of severe OHSS in high risk cases. For every 18 women at risk of severe OHSS albumin infusion will save one more case Albumin is a human product! D’Angelo et al., Cochrane Library, 2002

HES (Hydroxyethyl starch solution) administration Synthetic macromolecules used to prevent OHSS and avoid the potential risks from using human products such as albumin HES is effective volume expander. It is as effective as albumin It is cheaper and safer

Conclusion OHSS is a serious complication of ovarian stimulation The identification of high risk patients and in particular PCOS patients and the use of low dose protocols of ovarian stimulation have an important role in the prevention of OHSS To date no methods are available to completly prevent this complication except for withholding hCG.

Conclusion Coasting for at least as long as 3 days can be successfully used in the prevention of OHSS It appears that iv albumin administered at the time of oocyte retrieval may help the prevention of OHSS The effect of combining methods which act at two different levels (eq. coasting and HES administration) helps for a better prevention There is a clear need for large randomised studies